Lower alkyl quaternary ammonium salts of 2, 2, 4-trimethyl-alpha, alpha-diphenyl-1-pyrrolidinebutyramide



. 2,891,011 rowan ALKYL QUATE'RNARY AMMONIUM M SALTS or 2,2,4-'IRIMETHYL-a,a-DIPHENYL- l-PYRROLIDINEBUTYRAMIDE Brooke D. Aspergren and Robert B. Moifett, Kalamazoo, Mich, assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan .No Drawing. Application November 19, 1956 Serial No. 622,824

3 Claims. (or. 260-3263) are usefulintermediates for the preparation of 2,2,4-trimethy1-u,a-dipheny1-l-pyrrolidinebutyramide. lower-alkyl quaternary ammonium salts. The quaternary ammonium salts of the present invention possess excellent antispasmodic activity-and weak antisecretory activity.. This is in contrast to the activity shown by quaternary ammonium salts of closely related unsubstituted amides, i.e., primary amides, which do not have a combination of excellent antispa smodic activity and weak antisecretory activity, but instead combine, e.g., low antispasmodic with low antisecretory activity, or good antispasmodic with good antisecretory activity. Thus, the quaternary ammonium salts of the present invention are indicated for.

those situations in which pronounced antispasmodic activity is desired and antisecretory activity is held to a minimum. y.

The data given in Tablel are illustrative of the difierentiating eiiects noted above. The antispasmodic index was determined by intravenous administration to. Thiry-.

Vella dogs and equated to atropinej equals 1.0 (low values means low activity). The antisecretory activity was determined intravenously in rats and is given as the ED in mg./kg.--the effective dose necessary to reduce gastric secretion by fifty percent -(low values mean high activity). i

' The data in Table I show that 2,2,4-trimethyl-u,a-diphenyl-l-pyrrolidinebutyramide methobromide possesses an unique combination of properties which would not be expected from the properties of closely related corn-.

pounds including an adjacent homologue and an isomer.

Thus the quaternary ammonium salts of the invention possess a combination of unusually high antispasmodic activity and low antisecretory activity which is not possessed by the related compounds. For example, compounds A and C cqmbinelow antispasmodic activity with low antisecretory,activity mpompoundB on the other hand combines good"antispasmodic activity with an antisecretory activity about sixty times greater than that of the compound of the present invention.

2,891,071. Patented June 16,

I TABLE -I Anticholinergic Activity Compound i Antispas- Antlsecremodie tory Index Activity 0 .Br" il on, on. as 0.2

5 \CHQOHI +N i c i i Related Compounds A. O i Br' -NH: 1.0 0.2 1 /lScmon it 'B, o" Br i OH: on; 4.0 0.003

amou c. e y o Br "'NHQ in 0H; 1.0 0.2 cir,oH=- N C I 2,2,4 tritnethyl-oauadiphenyl 1 pyrrolidinebutyronitrile 'free base. 'This free base can be converted in known manner to acid addition salts such as the hydrochloride, hydrobromide, sulfate, acetate, phosphate, citrate, lactate, and the like. This'free baseor an acid addition salt thereof is hydrolyzed to produce 2,2,4-trin1ethyl-a,e-diphenyl-l-pyrrolidinebutyramide free base, according to the procedure of Cheney et al., J. Org. Chem. 17, 770 (1952). The desired 2,2,4 trimethyl-a,.a-diphenyl-bpyrrolidinebutyramide lower-alkyl quaternary ammonium" salts are thereupon produced by reacting the free base in an iiiertsolvent such as benzene with a quaternary ammonium salt-producing compound such as methyl:

chloride, methyl iodide, ethyl bromide, methyl bromide,

methyl p-toluenesulfonate, butyl iodide, ethyl sulfate,'; 7 The starting reactant, 1-(2'-" chloro ethyl) 2,ZA-trimethylpyrrolidine, "can readily be prepared from its hydrochloride, which in turn can be, prepared by reacting 2,2,4-trimethy1-1-pyrrolidineethanol hydrochloride with thionyl chloride [Mofiett etah,

ethyl iodide, and the'like.

The following example is illustrative of the process Example-Preparation of 2,2,4-trimethyl-oz,oz-diphenyl-1- pyrrolidinebutyramide methobromide A. 1- Z-CHLOROETHYL) -2,2,4-TRIMETHYLPYRROLIDIN E HYDROCHLORIDE Gaseous hydrogen chloride was passed into a solution of 42 grams (0.267 mole) .of 2,2,4-tiimethyl-1-pyrrolidine-ethanol (Molfet-t et al., supra) in 200 milliliters of benzene, with stirring and ice-bath cooling, until the solution was strongly acidic. With continued stirring and cooling, 24.5 grams (0.4 mole) of thionyl chloride was gradually added, and the reaction mixture was heated at reflux temperature for two hours. About fifty milliliters of solvent was removed by distillation and the mixture was cooled. The resulting crystalline 1-(2-chloroethyl) 2,2,4 trimethylpyrrolidine hydrochloride was collected, washed with anhydrous ether, and dried. The yield was 55.3 grams (98 percent); and the, compound melted at 162 to 1615 degrees centigrade. After recrystallization from isopropanol the product melted between 164 and 166 degrees centigrade.

Analysis.Calculated 'for C H Cl Na C, 50.95; H, 9.03; Cl, 33.42; N, 6.60. Found: C, 51029; H, 9.19; Cl, 33.22; N, 6.96.

-B. 2,2, l-TRIMETHYL-a,a-DIPHENYL-I-PYRROLIDINE BUTYRONITRILE FREE To a slurry of 7.0 grams of lithium amide in 400 milliliters of dry toluene was added 44.45 grams (0.23 mole) of diphenylacetonitrile in a threernecked, three-liter flask equipped with reflux condenser and stirrer, and the resulting mixture was stirred under reflux for four hours. A 48.7-gram (0.23 mole) portion of 1=(2-.chloroethyl)- 2,2,4-trimethylpy-rrolidine hydrochloride (Part A, this example) was converted to the free base by treatment with aqueous fifty percent sodium hydroxide solution, and the free base was extracted into 200 milliliters of toluene. This toluene solution was dried and gradually added to the aforesaid slurry, and the reaction mixture was heated at reflux temperature for eighteen hours. The mixture was cooled, washed with 300 milliliters of water, and then extracted with dilute hydrochloric acid prepared by mixing fifty milliliters of concentrated acid and 250 milliliters of water. The acid extract was made alkaline by adding 200 milliliters of twenty percent sodium hydroxide solution, and the mixture was extracted with benzene. The benzene extract was dried with anhydrous sodium sulfate, the benzene was removed by distillation, and the residual oil was distilled under reduced pressure. There was thus obtained 2,2,4-tflnflethYl-madiphenyl-lepyrrolidinebutyronitrile free base having a boiling point of 150 to 155 degrees centigrade at 0.05

millimeter pressure and 12 =1.5473.

Analysis-Calculated for C H N C, 83.08; H, 8.49; N, 8.43. Found: C, 81.99; H, 8.76; N, 8.91.

C. 2,2,4-T-JRIMETHYL-d,at-DLPHENYLJ-PYR.ROL;[DINE BUTYRONITRILE HYDROCHLORIDE hydrochloride having a melting point of 188 to 190 degreescentigrade. n y o C2aH29Ql 2? C, 1 .87; 7.29; N. 1. 9; 0.1 9.61. Fou d: ,0, 1. 90; m0;

Following the procedure Qfria Qabqva other acid a ator 4% addition salts such as 2,2,4-trirnethyl-a,m-diphenyl-1- pyrrolidinebutyronitrile sulfate, 2,2,4-trimethyl-a,a-diphenyl-l-pyrrolidinebutyronitrile hydrobromide, 2,2,4-trimethy1-u, x-diphenyl-l-pyrrolidinebutyronitrile acetate, 2, 2,4-trimethyl-a,a-dipheny1-l-pyrrolidinebutyronitrile phosphate, 2,2,4-trimethyl-a,a-diphenyl-l-pyrrolidinebutyronitrile citrate, 2,2,4-trimethyl-m,u-diphenyl-l-pyrrolidinebutyronitrile lactate, and the like, can be produced by substituting the corresponding acid for hydrogen chloride.

D. 2,2,4-TRIMETHYIra,a-DIPHENYL-l-PYRROLIDINE BUTYRAMIDE FREE BASE A solution of 154 milliliters of 98 percent sulfuric acid and 15.4 milliliters of water was added to ninety grams of 2,2. h h l m-di hsn pyrrolidinebutyronitrile hydrochloride, part C, in a oneliter, three-necked flask with stirrer and reflux condenser nd h m x ur wa ea e n a steam b th for ou hours. The reaction mixture was poured. Over crushed ice and made basic by the addition of one liter of concentrated ammonium hydroxide. The precipitate, 2,2,4-

trimethyl-or,a-diphenylel pyrrolidinehutyramide free base, was recovered by filtration, and was recrystallized from isopropanol. The yield was 69.5 grams (81.5 percent) and the product melted between and 127 degrees centigrade.

1 Afi ys -Ca culated r (32 1 301 20: 78. 51; 8-63; N. 8.00. Foun 0, 7.3.71: 8 9.822 E- 2; R THIr,G-DIP E XIrl-PYRB LHHNE B MZ E MEu HQ mM To a cold solution of eight grams of 2,2,4-trimethyla,u-diphenyl-1-pyrrolidinebutyramide free base, part D, in 100 milliliters of benzene was added fifty grams of cold methyl bromide. The mixture was allow ed to stand in a stoppered flask for 48 hours at about 25 degrees centigrade. The mixture was filtered and the reeovered precipitate was washed with ether and dried. This product, '2,2,4-trimethyl-m,a-diphenyl-lapyrrolidinebutyramide methobromide, weighed 9.8 grams (96 percent), ahd hald a melting point of 225 to 226 degrees centigrade.

Analysis.-Calculate d for 0 11 391 0; C, 64.71; H, 7.46; Br, 17.94; N, 6.29. Found: C, 64.73; H,

Br, 17.50; N, 6.13. 3

Following the procedure of part B, above, other loweralkyl quaternary ammonium salts such as 2 ,2 4-trim ethyllimited to the exactdetails of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the, and the invention is therefore to be only uy'ute scope of the appended claims. Weclaimz" 4 y 1. 2,2,4-trimethylc,WdiphenyI-1-pyrrolidinebutyramide free base. I i 2. 2,2,4-trimethylea, -diphenyl-lwpynrolidinebutyramide lower-alkyl quaternary ammoniumsa lt s.

3. 2,2,4-trimethyl-u, t-diphenyl-lwpyrrolidinebutyramide met-hobromide.

References Cited in the fileof this patent STA ES PATENTS 2, 82 206 Atheisrhs a1. 1.9. .1951 

2. 2,2,4-TRIMETHYL-A,A-DIPHENYL-1-PYRROLIDINEBUTYRAMIDE LOWER-ALKYL QUATERNARY AMMONIUM SLATS. 